Kynurenine emerges from the shadows-Current knowledge on its fate and function

Kynurenine (KYN), a main metabolite of tryptophan in mammals, is a direct precursor of kynurenic acid, anthranilic acid and 3-hydroxykynurenine (3-HK). Under physiological conditions, KYN is produced endoge-nously mainly in the liver by tryptophan 2,3-dioxygenase (TDO). Tumorigenesis and inflammatory conditions in-crease the activity of another KYN synthetizing enzyme, indoleamine 2,3-dioxygenase (IDO). However, knowledge about the exogenous sources and the fate of KYN in mammals is still limited. While most papers deal with the contribution of KYN to pathologies of the central nervous system, its role in the periphery has al-most been ignored. KYN is a ligand for the aryl hydrocarbon receptor (AhR). As a receptor for KYN and its down-stream metabolites, AhR is involved in several physiological and pathological conditions, including inflammation and carcinogenesis. Recent studies have shown that KYN suppresses immune response and is strongly involved in the process of carcinogenesis and tumour metastasis. Thus, inhibition of activity of the enzymes responsible for KYN synthesis, TDO, IDO or genetic manipulation leading to reduction of KYN synthesis, could be considered as innovative strategies for improving the efficacy of immunotherapy. Surprisingly, however, genetic or pharmaco-logical approaches for reducing tryptophan catabolism to KYN do not necessarily result in decrease of KYN level in the main circulation. This review aims to summarize the current knowledge of KYN fate and function and to emphasize its importance for vital physiological and pathological processes. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

KYN, a main metabolite of tryptophan produced mainly in the liver by TDO under physiological conditions, is also synthesized by IDO in diseases. While KYN's role in central nervous system pathologies is well studied, its functions in the periphery are less explored.